Development of a broadly effective HIV-12 immunotherapy has been limited because of the inherent structural properties the HIV envelope expressed on the native virion. HIV infection involves a series of stepwise changes in env antigenic structures and epitope presentation during which the virus unfolds and exposes neutralizing epitopes in close proximity to the target cell surface structure. We propose, that it is difficult for the immune system to respond in a higher order integration in which an antibody response an modify the envelope to expose and then recognize exposed neutralizing epitopes. This higher integration must be imposed on the immune system through active or passive immunization in which multiple classes of antibodies are induced or included which together mediate viral neutralization, we have used an assay incorporating primary isolate virions. When serum from clade B infected individuals was tested for IgG antibodies, 36% of infected individuals captured virus but only 7% of these individuals captured significant quantities of virus. Virion specific antibody correlated with CD4 counts, and of more significance, primary isolate neutralization. The low prevalence of antibodies reactive with primary isolate virions may be related to the general inability of sera to neutralize primary isolates. Most studies to date have utilized clade B isolates with relatively little information as to neutralizing antibody responses to isolates of other clades. Since infection with clade C accounts for over half of the infections wold-wide, we propose to isolate and characterize human monoclonal antibodies reactive with clade C primary isolate virions to study the neutralizing antibody response in these infections. These antibodies will be further studied for passive immunization against mucosal challenge in neonatal macaques. Determinations of the efficacy of the these antibodies for passive immunization will facilitate the design of broadly effective active vaccine therapies.